The overall objective of this Program Project is to identify and refine strategies for the prevention, diagnosis, and treatment of dengue. Dengue remains a significant global public health burden, particularly in resource-poor countries of tropical and subtropical regions of the world, as well as an NIAID biodefense research priority agent. We hypothesize that dengue-related morbidity and mortality result from a sequence of events involving the individual and the community and influenced by both viral and host factors, each of which may be amenable to intervention. This research program involves a coordinated series of epidemiologic, clinical, virologic, and immunologic investigations, to be conducted by an experienced team, extending an established track record of productive research collaboration and building on a superb research infrastructure. Project 1 will involve clinical, virologic, and immunologic studies of subjects with suspected acute dengue illness to define optimal strategies for triage and management of adult and pediatric patients and test novel non-invasive monitoring approaches. Project 2 will involve prospective field epidemiologic studies to define relationships between individual and herd immunity and dengue virus (DENV) circulation and their implications for vaccine introduction. Project 3 will define immunologic correlates of protective and pathogenic immunity in natural DENV infections and in subjects in a phase III dengue vaccine trial. Three Cores will provide common infrastructure to support all three projects: Administration, Data Management and Statistics, and Clinical Research Laboratory. Interactions between the projects and cores, with exchange of research material, data, and concepts, will create synergy as a scientific program. The findings from these proposed research studies should have broad basic science as well as clinical and public health implications.